Novel strategy to mitigate and treat radiation combined infection injury by targe

靶向减轻和治疗放射复合感染损伤的新策略

• 批准号: 7559943
• 负责人: Shyam Biswal
• 金额: $ 20.5万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-21 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7559943
• 关键词: 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; Abdomen; Accidents; Acetaminophen; Acute; Aftercare; Antioxidants; Apoptosis; Appendix; Area; Attenuated; Bacteremia; Bacteria; Bacterial Infections; Bacterial Translocation; Bioinformatics; Biological; Biological Markers; Bleomycin; Blood Cells; Blood Circulation; Brain; Burn injury; Calculi; Carcinogens; Cells; Cerebral hemisphere hemorrhage; Chronic; Clinical; Clinical Management; Colitis; Cytomegalovirus; DNA Damage; Data; Development; Dextran Sulfate; Disease; Disruption; Dissociation; Dose; Drug Kinetics; Drug effect disorder; Emergency Situation; End Point; Endotoxins; Enzymes; Epithelial; Epithelial Cells; Esters; Ethical Issues; Etiology; Event; Failure; Fibrosis; Functional disorder; Gastrointestinal Injury; Gastrointestinal tract structure; Gene Expression; Genes; Genetic; Genetic Models; Genomics; Glucose; Glutamate-Cysteine Ligase; Glutathione; Glutathione S-Transferase; Gram-Negative Bacteria; Gram-Positive Bacteria; Hematopoietic; Hematopoietic System; Host Defense; Human; Immune; Immune response; Immunohistochemistry; Incidence; Individual; Infection; Inflammation; Inflammatory; Injury; Integration Host Factors; Intestines; Ionizing radiation; Kidney; Lead; Ligation; Link; Liver; Longitudinal Studies; Lung; Maryland; Measurement; Modeling; Morbidity - disease rate; Mus; Myelosuppression; NADP; Natural regeneration; Nuclear; Nuclear Translocation; Organ; Organ failure; Outcome; Oxidants; Oxidation-Reduction; Oxidative Stress; Oxidoreductase; Pathway interactions; Permeability; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Pneumonia; Predisposition; Prohibit; Proteins; Proteomics; Protocols documentation; Pseudomonas aeruginosa; Public Health; Public Health Schools; Radiation; Radiation Injuries; Radiation Interaction; Radiation Syndromes; Reactive Oxygen Species; Readiness; Regulation; Reperfusion Injury; Research; Risk; Rodent; Sepsis; Serum; Severities; Specificity; Staging; Streptococcus; Streptococcus pneumoniae; Stress; Structure; Syndrome; System; Tamoxifen; Target Populations; Terrorism; Testing; Therapeutic; Thioredoxin; Time; Tissues; Toxic effect; Translating; Treatment Protocols; Universities; Villus; War; Western Blotting; Whole-Body Irradiation; Wild Type Mouse; base; carcinogenesis; cigarette smoke-induced; concept; dosage; drug efficacy; gastrointestinal; glutathione peroxidase; heme oxygenase-1; improved; inhibitor/antagonist; irradiation; lung injury; mortality; mouse model; multiorgan injury; nonhuman primate; novel; novel strategies; novel therapeutics; nuclear factor-erythroid 2; pre-clinical; prognostic; programs; radiation effect; research study; response; secondary infection; small molecule; synergism; therapeutic target; transcription factor

DESCRIPTION (provided by applicant): The risk of civilians or emergency responders being exposed to ionizing radiation is high in scenarios of nuclear/radiological terrorism or accidents. Reactive oxygen species and electrophiles generated after radiation exposure is involved in impaired immune response due to depletion of hematopoietic immune cells and loss of mucosal barriers, predisposing an individual to secondary infection by opportunistic bacteria and exacerbate radiation-induced morbidity and mortality driven by sepsis. There is an urgent need to develop effective therapies to mitigate synergistic effects of radiation and infection, which can be translated to mass casualty response. Our studies have shown that redox sensitive transcription factor, nuclear factor-erythroid 2 p45-related factor 2 (NRF2) protects against inflammatory disorders caused by environmental oxidants and bacterial infection by inhibiting oxidative stress. Dissociation of the transcription factor from its inhibitor, KEAP1 by electrophiles or oxidants causes nuclear translocation of NRF2 and transcriptional induction of antioxidant genes - glutathione pathway, thioredoxin pathway, heme oxygenase-1, several protective pathways that collectively protect against oxidative stress and macromolecular damage. Our research provides strong rational to hypothesize that "enhancing the Nrf2 pathway will mitigate multi-organ injury by attenuating oxidative stress and improve survival following radiation-combined infection injury". The R21 phase will investigate the strategy of enhancing the Nrf2 pathway to mitigate multi-organ injury and improve survival following radiation-combined bacterial infection injury in mice models by genetic approach (using inducible deletion of Nrf2 inhibitor, KEAP1) and small molecule approach (using a potent Nrf2 activator, CDDO-Me [methyl ester derivative of 2- cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO)] that has undergone phase I clinical trial). Based on a positive outcome of intervening radiation-combined injury using Nrf2 activator, the R33 phase will focus on development of optimal treatment regimen and prognostic biomarkers of Nrf2 based therapy using CDDO-Me in mice model and then perform proof of concept studies in nonhuman primate model focusing on post-radiation induced gastrointestinal injury. These studies promise to develop a novel strategy to mitigate radiation- combined injury that can be used as an effective countermeasure in target population. Page 1 of 1 Public Health Relevance Statement Novel therapy for mitigating and treating radiation as well as radiation combined infection injury is urgently warranted because they present a huge public health problem in radiological/nuclear war /accident scenario. Other than clinical management, currently there are no effective therapies that can be translated to mass causality during a nuclear attack. This application is focused on development of a novel strategy for treating radiation injury by targeting a host defense factor.

描述（由申请方提供）：在核/放射性恐怖主义或事故的情况下，平民或应急人员暴露于电离辐射的风险很高。辐射暴露后产生的活性氧和亲电体参与造血免疫细胞耗竭和粘膜屏障丧失导致的免疫应答受损，使个体易受机会性细菌继发感染，并加剧辐射诱导的败血症导致的发病率和死亡率。迫切需要开发有效的疗法，以减轻辐射和感染的协同效应，这种效应可以转化为大规模伤亡反应。我们的研究表明，氧化还原敏感的转录因子，核因子-红细胞2 p45相关因子2（NRF 2）通过抑制氧化应激来保护免受环境氧化剂和细菌感染引起的炎症性疾病。通过亲电体或氧化剂将转录因子从其抑制剂KEAP 1解离，导致NRF 2的核转位和抗氧化基因的转录诱导-谷胱甘肽途径、硫氧还蛋白途径、血红素加氧酶-1、共同保护免受氧化应激和大分子损伤的几种保护性途径。我们的研究提供了强有力的理由来假设“增强Nrf 2通路将通过减弱氧化应激减轻多器官损伤并改善放射联合感染损伤后的存活率”。R21阶段将通过遗传学方法研究增强Nrf 2通路以减轻多器官损伤并改善小鼠模型中辐射联合细菌感染损伤后的存活率的策略（使用Nrf 2抑制剂KEAP 1的诱导性缺失）和小分子方法（使用有效的Nrf 2激活剂，CDDO-Me [2-氰基-3，12-二氧代齐墩果-1，9（11）-二烯-28-酸的甲酯衍生物（CDDO）]，其已经历I期临床试验）。基于使用Nrf 2激活剂干预辐射联合损伤的积极结果，R33阶段将专注于在小鼠模型中使用CDDO-Me开发基于Nrf 2的治疗的最佳治疗方案和预后生物标志物，然后在非人灵长类动物模型中进行概念验证研究，重点是辐射后诱导的胃肠道损伤。这些研究有望发展一种新的策略，以减轻放射复合损伤，可作为一个有效的对策，在目标人群。第1页，共1页公共卫生相关性声明缓解和治疗辐射以及辐射合并感染损伤的新疗法是迫切需要的，因为它们在辐射/核战争/事故情况下构成了巨大的公共卫生问题。除了临床管理，目前还没有有效的治疗方法可以在核攻击期间转化为大规模因果关系。本申请集中于通过靶向宿主防御因子来治疗辐射损伤的新策略的开发。